Parkinson's disease is a common progressive neurodegenerative disorder that affects 2% of the adult population. The loss of dopamine producing neurons in the substantia nigra pars compacta results in such symptoms as a resting tremor, slow movement, rigidity and unstable posture. The death of the dopaminergic neurons has been proposed to be due to aggregation of the protein 1-synuclein. An improved targeted delivery system to neuronal cells is necessary to improve therapeutic treatment options. Physical Sciences Inc. (PSI) proposes to conjugate a targeted small interfering RNA (siRNA) against 1- synuclein protein to a carrier molecule for specific delivery to neurons. The Phase II effort will develop an effective method for large-scale production of the siRNA conjugate and will evaluate the most efficient mode of in vivo delivery in live animal models. We anticipate that the proposed system will deliver sufficient siRNA to reduce the production of 1-synuclein by at least 80%.Project Narrative Relevance to public health. Limited treatment options are available to patients with Parkinson's disease. 1-Synuclein has been proposed to be a causative agent of deleterious effects of Parkinson's disease. The technology developed during the proposed research will reduce the production of 1-synuclein in nerve cells and should therefore slow the progression of the disease. [unreadable] [unreadable] [unreadable]